Is MECP2 p.Pro411Ser (c.1231C>T) pathogenic?

MECP2 p.Pro411Ser (c.1231C>T) is classified Likely benign in MECP2 (ClinVar, Expert panel, 5 submitters; last evaluated 2022-12-09). AlphaMissense: likely benign (0.0737); Very rare (popmax 0.00441%, amr); Associated with Rett syndrome.

What condition is associated with MECP2 p.Pro411Ser (c.1231C>T)?

MECP2 p.Pro411Ser (c.1231C>T) is associated with Rett syndrome, severe neonatal-onset encephalopathy with microcephaly (ClinVar).

How common is MECP2 p.Pro411Ser (c.1231C>T) in the general population?

MECP2 p.Pro411Ser (c.1231C>T) is very rare (popmax 0.00441%, amr) (gnomAD).

How is Rett syndrome inherited?

Typically X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about MECP2 p.Pro411Ser (c.1231C>T)?

AlphaMissense predicts likely benign (score 0.0737) — an in-silico prediction, not a clinical call.

MECP2 p.Pro411Ser

c.1231C>T · rs797045691 · VCV211454

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0737 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Rett syndrome

ClinGen expert panel — Rett and Angelman-like Disorders VCEP

Likely Benign for Rett syndrome. Applied ACMG criteria (verbatim):

BS1 BS2_Supporting

Curation rationale (ClinGen, verbatim)

The allele frequency of the p.Pro399Ser variant in MECP2 (NM_004992.3) is 0.01% in Latino/Admixed American sub population in gnomAD, which is high enough to meet the BS1 criteria based on thresholds defined by the ClinGen Rett/Angelman-like Expert Panel for Rett/AS-like conditions (BS1). The p.Pro399Ser variant is observed in 1 unaffected individual (internal database) (BS2_supporting). In summary, the p.Pro399Ser variant in MECP2 is classified as a Likely Benign based on the ACMG/AMP criteria (BS1, BS2_supporting).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0737	likely benign
REVEL	0.256	benign-leaning
SaProt	LLR -5.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.55	unconstrained · MANE · 1,052 bp · p 2.6e-22 · regional, not allelic
Overall
CADD	16.87	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P399S vs ClinVar P411S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00441% Admixed American · 2/45,374 alleles

Filtering AF 0.00126% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00166% 20/1,201,343 alleles · very rare exomes 16/1,093,362 · genomes 4/107,981 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00441%	22,687
European (non-Finnish)	0.00202%	49,626

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MECP2
Protein: p.Pro411Ser
Coding: c.1231C>T
MANE Select: NM_001110792
dbSNP: rs797045691
Type: single nucleotide variant
Location: chrX:154030633 (GRCh38)
Structure: AlphaFold pLDDT 57.25 · 11 PDB
Residue 399 UniProt numbering: a UniProt-annotated variant site (in rtt); the 'disordered' region; a UniProt-annotated variant site (in mrxs13; likely benign)

Full MECP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Rett syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: severe neonatal-onset encephalopathy with microcephaly

For Rett syndrome (Orphanet):

Inheritance: X-linked dominant
Onset: Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

MECP2 p.Pro411= Benign/Likely benign ★★ same residue
MECP2 p.Pro411Leu Benign/Likely benign ★★ same residue
MECP2 p.Pro411fs Pathogenic ★ same residue
MECP2 c.414-3C>G Pathogenic ★★★ same condition
MECP2 c.62+1G>A Pathogenic ★★★ same condition
MECP2 c.62+2T>G Pathogenic ★★★ same condition
MECP2 p.Ala143Asp Pathogenic ★★★ same condition
MECP2 p.Ala291Val Likely pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mecp2-p-pro411ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown